The underlying pathology of cataract can often be demonstrated to involve defects in the differentiation of lens fiber cells from their proliferative transitional zone precursors. Further, the side effects of cataract surgery such as posterior capsular opacification and Soemmering's ring formation can reduce the long term visual outcome for patients, particularly those fitted with the newest generation of accommodating intraocular lenses. These studies seek to elucidate the transcriptional mechanisms responsible for normal lens fiber cell differentiation and the transcriptional response of lens cells to injury, especially following cataract extraction. Specific aim one seeks to determine the molecular mechanisms that allow Prox1 to function as both a transcriptional activator and repressor. Since Prox1 is essential for lens fiber cell differentiation, this will allow us to determine how Prox1 regulates its diverse functions. Specific aim two seeks to investigate how transcription factors of the Zeb family participate in lens development and tests the hypothesis that these factors also participate in the lens injury response. These investigations will determine how the molecular mechanisms controlling lens development are reused following lens injury. Specific aim three seeks to determine the function of HMGN proteins in the lens. Since these proteins are known to be involved in chromatin remodeling resulting in gene activation, these studies will allow us to understand how the enormous transcriptional activity of crystallins is accomplished. These complementary studies should provide insight into how lens fiber cell differentiation is controlled and how this process is co-opted following lens injury. PUBLIC HEALTH RELEVANCE: Cataracts are the most prevalent form of blindness worldwide. In the USA, cataract removal is the most common outpatient surgical operation performed on the elderly costing over 343 million dollars in 2005 (http://www.cms.hhs.gov/MedicareMedicaidStatSupp/). However, 10- 20% of elderly and nearly 100% of pediatric patients treated for cataract develop posterior capsular opacification (PCO) which requires additional treatments and can result in reduced visual outcomes. Further, much effort is being exerted towards the development of intraocular lens (IOLs) implants that restore the ability of the eye to accommodate (establish near focus) after cataract surgery. A major impediment to long term restoration of accommodation is that lens epithelial cells trapped at the lens equator by the IOL often regenerate the lens cortex which reduces the ability of the ciliary muscles to accommodate the implanted IOL. This proposal addresses unanswered questions related to the molecular mechanisms of PCO development and lens fiber cell differentiation with the long term goal of preventing the side effects of cataract surgery.